EP0151528B1

EP0151528B1 - 5-(amino or substituted amino)-1,2,3-triazoles

Info

Publication number: EP0151528B1
Application number: EP85300520A
Authority: EP
Inventors: Elbert E. Harris; Richard L. Tolman
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1984-02-02
Filing date: 1985-01-25
Publication date: 1990-07-04
Anticipated expiration: 2005-01-25
Also published as: JPS60188375A; AU598067B2; AU3829985A; ZA85785B; EP0151528A2; NZ210983A; JPH0625171B2; EP0151528A3; DE3578499D1; AU8203087A

Description

This invention relates to triazole compounds, their preparation, and their use.
Various 5-amino-4-substituted 1,2,3-triazoles with a 5-N-aryl or 1-aryl substituent are disclosed in II Farmaco, Vol 34, No 3, 1979, pages 217-228, and Vol 35, No 4, 1980, pages 298-307 and 308-232; in J.C.S. (1971) No 4, pages 706-713, (1969) No 1, 152-160 and (1974) No 17, pages 2030-2036; and in Chem. Abs., Vol 91 No 24, 204219s.
Coccidiosis is a wide-spread poultry disease which is produced by infections of protozoa of the genus Eimeria which causes severe pathology in the intestines and caeca of poultry. Some of the most significant of these species are e. tenella, E. acervulina, E. necatrix, E. brunetti, E. maxima, E. mitis, E. mivati, E. hagani and E. praecox. This disease is generally spread by the birds picking up the infectious organism in droppings on contaminated litter or ground or by way of food or drinking water. The disease is manifested by hemorrhage, accumulation of blood in the caeca, passage of blood to the droppings, weakness and digestive disturbances. The disease often terminates in death, but the market value of fowls that survive severe infections is substantially reduced. Coccidiosis is therefore a disease of great economic importance and extensive work has been done to find new and improved methods for controlling and treating coccidial infections in poultry.
None of the 1,2,3-triazole compounds in the documents mentioned above has any anti-coccidial activity, although US Patent Specification US-A-3 577 553 discloses the anti-coccidial nature of certain 1,3,4-triazoles, viz. compounds of the formula
where Tz is 1,3,4-triazol-1-yl, R is hydrogen, C_1-5 alkyl or C_1-5 haloalkyl, and Ar is a phenyl or styryl radical, optionally having one or two C_1-5 alkyl, C_1-5 alkoxy, C_1-5 alkylthio, trifluoromethyl, trifluoromethoxy, nitro or halogen substituents in the ring.
The invention is based on the discovery that certain 5-amino-1,2,3-triazoles and their substituted derivatives have a surprisingly and unexpectedly high degree of activity against coccidiosis of poultry. Certain of the compounds are novel.
The compounds used anti-coccidially in accordance with this invention have the following structural formula:
in which R₁ is phenyl or phenyl-(C₁-₃ alkyl), either unsubstituted or having from one to five halogen, cyano, trifluoromethyl, C_1-3 alkanoyl, nitro, C₁-₃ alkyl, C₁-₃ alkoxy, carboxy, alkyoxycarbonyl, trifluoromethoxy, acetamido, C₁-₃ alkylthio, C_1-3 alkylsulphinyl, C_1-3 alkylsulphonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulphinyl and/or trifluoromethylsulphonyl substituents; or is phenacyl, pyridyl, pyridylmethyl, naphthyl, naphthylmethyl, quinolyl or quinolylmethyl; R₂ is amino, C_1-3 alkylamino, di(C_1-3 alkyl)amino, acetamido, acetamido, ureido, formamido, formimido or guanidino; and R₃ is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl.
In the novel compounds of the present invention, R₁ is a benzyl radical having a trichlorovinyl substituent and none, one or two substituents as defined above, all the substituents being in the meta or para position.
Preferably, in the anticoccidial compounds R₂ is amino, R₃ is carbamoyl, and R₁ is phenyl or benzyl having one, two or three substituents that are halogen, cyano, trifluoromethyl, trichlorovinyl and/or methyl; especially di- or substituted phenyl or di- or tri-substituted benzyl in which the substituents are in the meta or para positions and are chloro, cyano, methyl, trifluoromethyl, or trichlorovinyl.
Examples of preferred compounds for anti-coccidial use in accordance with this invention are:

5-amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide,
5-amino-1-(3,4,5-trichlorobenzyl)-1,2,3-triazole-4-carboxamide,
5-amino-1-(4-chloro-3-trifluoromethylbenzyl)-1,2,3-triazole-4-carboxamide,
5-amino-1-(4-trichlorovinylbenzyl)-1,2,3-triazole-4-carboxamide. Only the last-mentioned is novel and per se forms part of the present invention.

The C₁-₃ alkyl groups comprise methyl, ethyl, propyl and isopropyl; the C_1-3 alkoxy groups comprise methoxy, ethoxy, propoxy, and isopropoxy; the C₁-₃ alkanoyl groups comprise formyl, acetyl, and propionyl.
Administration of a small amount of at least one compound preferably by combination with poultry feed, is effective in preventing or greatly reducing the incidence of coccidiosis. The compounds are effective against both the caecal form (caused principally by E. tenella) and the intestinal forms (principally caused by E. acervulina, E. brunetti, E. maxima and E. necatrix). The coccidiostats of this invention are particularly effective against the species that caused caecal damage in addition to preventing the pathology caused by the coccidia. Compounds of the invention are also active against Eimeria spp, in other animals.
The compounds may be prepared by any one of several processes. The most general process is outlined in the following reaction scheme.
An R₃-methylene substituted nitrile is allowed to react with an R, azide in the presence of a base to provide the desired 5-amino-1-substituted-1,2,3-triazole. The reaction is carried out in solvents such as aromatic hydrocarbons, lower alkanols, dimethylformamide, dimethylsulphoxide or hexamethylphosphortriamide. The base may be any alkali metal or alkaline-earth metal hydroxide, alkoxide or hydride such as sodium ethoxide, potassium t-butoxide, magnesium ethoxide, sodium hydroxide or sodium hydride, chosen to be compatible with the reaction solvent. Generally the reaction is conducted at from -40°C to 100°C and is complete in from 15 minutes to 48 hours. The product of the reaction is isolated by known techniques.
where X is a halogen, preferably chlorine or bromine. A 1-unsubstituted but otherwise appropriately substituted 1,2,3-triazole is reacted with an R₁ halide in the presence of a base to prepare the desired 1- substituted 1,2,3-triazole. The reaction is carried out in a solvent which may be any polar aprotic organic solvent such as dimethylformamide, dimethylsulphoxide, acetonitrile or dioxane in the presence of a base, which may be any non-nucleophilic organic or inorganic base. Suitable inorganic bases are alkali metal bases, such as sodium and potassium carbonates, phosphates, bicarbonates and hydroxides, and sodium hydride. The base is chosen for compatibility with the reaction solvent. Suitable organic bases are tertiary amines such as trialkyl-substituted amines. The reaction rate varies greatly with the nature of the proposed substituent at the R₁ position, the base and the solvent. Very reactive substituent and base combinations may take as little as ten minutes: at the other extreme, the reaction may take as long as two weeks. Most reactions are however complete in from 1 to 100 hours. The reaction is carried out at a temperature of from room temperature to 100°C or to the reflux temperature of the solvent system being used. The products of the reaction are isolated using known techniques.
The novel compounds of this invention are orally administered to poultry for the control and prevention of coccidiosis. Any number of conventional methods are suitable for administering the coccidiostats of this invention to poultry, for example, they may be given in the poultry feed, which is most convenient, or their drinking water. The actual quantity of the coccidiostats administered to the poultry and the concentration in the feed will vary over a wide range and be adjusted to individual needs, depending upon species of the coccidia involved and severity of the infection. The limiting criteria are that the minimum amount be sufficient to control coccidiosis and the maximum amount be such that the coccidiosis does not cause any undesirable effects.
A feed typically contains from 0.001 to 0.2 percent, preferably from 0.003 to 0.1 percent, by weight of one of the coccidiostats of this invention. The optimum levels will naturally vary with the specific compound utilized and species of Eimeria involved, and can be readily determined by one skilled in the art. Levels of from 0.003 to 0.1 percent by weight of the diet are especially useful in controlling the pathology associated with E. tenella, as well as the intestinal dwelling species.
Depending on the compound used, levels as low as 0.001 percent possess the novel effects of reducing the number of oocysts passed in the droppings of infected chickens.
The novel coccidiostats of the invention may be readily dispersed by mechanically mixing them in finely ground form with the poultry feed, or with an intermediate formulation (premix) that is subsequently blended with other components to prepare the final poultry feed. Typical components of poultry feeds include molasses, fermentation residues, corn meal, ground and rolled oats, wheat shorts and middlings, alfalfa, clover and meat scraps, together with mineral supplements such as bone meal and calcium carbonate and vitamins.
The following non-limiting examples will serve to further illustrate the invention.

Example 1

5-Amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide

Method A

A stirred mixture of 3,4-dichlorobenzyl chloride (12.6 g, 64.5 mmol) and sodium azide (7.0 g, 0.11 mole) in absolute ethanol (70 ml) was refluxed for 4.75 hours, cooled and filtered to provide a solution of 3,4-dichlorobenzyl azide. Separately, 2-cyanoacetamide (5.5 g, 65 mmol) was added to a 35°C solution of sodium (1.5 g, 65 mmol) in absolute ethanol (125 ml), and to the resulting suspension was added the above azide solution dropwise over 10 minutes. The combined mixtures were refluxed for 1 hour, kept 16 hours at ambient temperature and 1 hour at 5°C, and filtered. The crude product was dried under vacuum, dissolved in boiling ethanol (290 ml), filtered hot, and cooled to 0°C. The solid was collected by filtration and dried under vacuum to provide 12.4 g (67%) of 1-(3,4-dichlorobenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p. 221-222°C.

Method B

A stirred, ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (635 mg, 5.00 mole) in dry dimethylformamide (20 ml) is treated in one portion with sodium hydride (240 mg of a 50% dispersion in mineral oil, 120 mg NaH, 5.0 mmol). After 15 min 3,4-dichlorobenzyl chloride (0.977 g, 5.00 mmol) is added. The mixture is stirred 1 hour, poured into water (20 ml), acidified to pH 6 with glacial acetic acid, and filtered. The solid is washed with water, dried, and chromatographed to provide 5-amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide.

Example 2

5-Amino-1-(4-methylbenzyl)-1,2,3-triazole-4-carboxamide

A stirred mixture of 4-methylbenzyl bromide (1.3 g, 7.0 mmol) and sodium azide (754 mg, 11.6 mole) in ethanol (8 ml) was refluxed under a nitrogen atmosphere for 3 hours, cooled to ambient temperature, and filtered. Separately, 2-cyanoacetamide (588 mg, 7.0 mmol) was added to a stirred, refluxing solution of sodium (167 mg, 7.2 mmol) in ethanol (15 ml), followed by dropwise addition of the above azide solution over 20 min. The resulting slurry was refluxed 1 hour, cooled to ambient temperature, and refrigerated. The precipitate was collected by filtration, washed with ethanol, and dried under vacuum to provide 1.12 g (69%) of 1-(4-methylbenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p. 223-225°C.

Example 3

4-Chloro-3-cyanobenzyl bromide

A mixture of 2-chloro-5-methylbenzonitrile (10.6 g, 69.9 mmol), N-bromosuccinimide (12.2 g, 68.5 mmol) and dibenzoyl peroxide (349 mg, 1.44 mmol) in benzene (350 ml) was refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was suspended in 7:3 (v/v) hexane-dichloromethane, filtered, and evaporated. The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane to provide 4.8 g (30%) 4-chloro-3-cyanobenzyl bromide, m.p. 55-58°C.

Example 4

4-Chloro-3-cyanobenzyl azide

A stirred mixture of 4-chloro-3-cyanobenzyl bromide (3.0 g, 13 mmol), and sodium azide (1.26 mg, 19.4 mmol) was refluxed 5 hours in absolute ethanol (30 mL). The mixture was kept 18 hours at ambient temperature, filtered, and the filtrate was evaporated under vacuum. The residue was triturated with diethyl ether, filtered, and evaporated to provide 2.45 g (98%) liquid 4-chloro-3-cyanobenzyl azide; I.R. (neat): 2240, 2100 cm'.

Example 5

5-Amino-1-(4-chloro-3-cyanobenzyl)-1,2,3-triazole-4-carboxamide

A stirred suspension of 2-cyanoacetamide (790 mg, 9.40 mmol) in absolute ethanol (40 ml) was treated with sodium methoxide (495 mg, 9.16 mmol) and refluxed 10 minutes. The mixture was cooled slightly, a solution of 4-chloro-3-cyanobenzyl azide (1.35 g, 7.01 mmol) in absolute ethanol (10 ml) was added in one portion, and the mixture was refluxed 2.5 hours. The mixture was filtered hot, the solid was washed with absolute ethanol, and the combined filtrate and wash were evaporated to dryness under vacuum. The residue was triturated with diethyl ether, filtered, and washed twice with diethyl ether. The solid was recrystallized from methanol (6 ml) and dried at 65°C under vacuum to provide 635 mg (24%) 5-amino-1-(4-chloro-3-cyanobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 172-175°C.

Example 6

1-(3,4-Dichlorobenzyl)-5-methylamino-1,2,3-triazole-4-carboxamide

A mixture of 5-amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide (2.66 g, 10.0 mmol), methyl iodide (1.42 g, 10.0 mmol), and potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylformamide (20 ml) is stirred 48 hours at ambient temperature, poured into water (150 ml), and filtered. Chromatography provides 1-(3,4-dichlorobenzyl)-5-methylamino-1,2,3-triazole-4-carboxamide.

Example 7

5-Amino-1-(4-chloro-3-cyanobenzyl)-1,2,3-triazole-4-carboxamide

A stirred suspension of 2-cyanoacetamide (790 mg, 9.4 mmol) in absolute ethanol (40 ml) was treated with sodium methoxide (495 mg, 9.2 mmol) and refluxed 10 minutes. The mixture was cooled lightly, a solution of 4-chloro-3-cyanobenzyl azide (1.35 g, 7.0 mmol) in absolute ethanol was added, and the mixture was refluxed 2.5 hours. The mixture was filtered hot, and the filtrate evaporated under vacuum. The residue was triturated with diethyl ether, filtered, and washed twice with diethyl ether. The solid was recrystallized from refluxing methanol, filtered, washed twice with methanol and once with diethyl ether, and dried at 65°C under vacuum to provide 635 mg (33%) 5-amino-1-(4-chloro-3-cyanobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 172-175°C.

Example 8

5-Amino-1-(4-cyano-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide

A stirred, ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (630 mg, 5.0 mmol) in dry N,N-dimethylformamide (20 ml) was treated with sodium hydride (250 mg of a 50% dispersion in mineral oil, 125 mg NaH, 5.2 mmol). The resulting suspension was stirred 10 min., 4-cyano-3,5-dichlorobenzyl chloride (1.1 g, 5.0 mmol) was added, and the mixture was stirred 2 hours. The reaction was quenched by pouring into ice and water (80 ml). The suspension was filtered and washed three times with water. The solid was suspended in 19:1 (v/v) dichloromethane-methanol and filtered to provide 364 mg (23%) 5-amino-1-(4-cyano-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide. Recrystallization from ethanol provided material of m.p. 238-239.5°C.

Claims

1. A compound having the formula:

in which R₁ is a benzyl radical having a trichlorovinyl substituent and none, one or two halogen, cyano, trifluoromethyl, C₁-₃ alkanoyl, nitro, C₁-₃ alkyl, C_i-₃ alkoxy, carboxy, alkoxycarbonyl, trifluoromethoxy, acetamido, C₁-₃ alkylthio, C_1-3 alkylsulphinyl, C₁-₃ alkylsulphonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulphinyl and/ortrifluoromethylsulphonyl substituents; R₂ is amino, C_1-3 alkylamino, d(C_1-3 alkyl)amino, acetamido, ureido, formamido, formimido or guanidino; and R₃ is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl.

2. A compound as claimed in Claim 1 in which R₁ is a benzyl radical having a trichlorovinyl substituent and none, one or two substituents that are halogen, cyano, trifluoromethyl, trichlorovinyl and/or methyl; R₂ is amino and R₃ is carbamoyl.

3. 5-amino-1-(4-trichlorovinylbenzyl)-1,2,3-triazole-4-carboxamide.

4. A method of preparing a compound as claimed in Claim 1 in which R₂ is amino by reaction of a monosubstituted acetonitrile R₃CH₂CN with an azide R₁N₃ in the presence of an alkali metal or alkaline-earth metal hydroxide, alkoxide or hydride in a compatible solvent.

5. A method as claimed in claim 4 in which the monosubstituted acetonitrile is 2-cyanoacetamide, malononitrile, or a lower alkyl ester of cyanoacetic acid.

6. A method of preparing a compound as claimed in Claim 1 comprising reacting a compound as claimed in Claim 1 except that R₁ is hydrogen with an R₁ halide in the presence of a non-nucleophilic organic or inorganic base and in a compatible polar aprotic organic solvent.

7. A method of preparing a compound as claimed in Claim 1 in which R₂ is C_1-3 alkyl amino or di(C_1-3 alkyl)amino comprising reacting a compound as claimed in Claim 1 in which R₂ is amino with a C_1-3 alkyl halide in the presence of a non-nucleophilic organic or inorganic base and in a compatible polar aprotic organic solvent.

8. A compound having the formula

in which R, is phenyl or phenyl-(C_1-3alkyl), either unsubstituted or having from one to five halogen, cyano, trifluoromethyl, C_1-3 alkanoyl, nitro, C₁-₃ alkyl, C_1-3 alkoxy, carboxy, alkoxycarbonyl, trifluoromethoxy, acetamido, C₁-₃ alkylthio, C₁-₃ alkylsulphinyl, C_1-3 alkylsulphonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulphinyl and/or trifluoromethylsulphonyl substituents; or is phenacyl, pyridyl, pyridylmethyl, naphthyl, naphthylmethyl, quinolyl or quinolylmethyl; R₂ is amino, C_1-3 alkylamino, di(C_1-3 alkyl) amino, acetamido, ureido, formamido, formimido or guanidino; and R₃ is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl, for use in the prevention or treatment of coccidiosis.

9. A composition useful for the prevention and treatment of coccidiosis which comprises an inert carrier and a compound having the formula set forth in Claim 8.